This proposal seeks crucial support for The Bipolar Sequencing Consortium (BSC), which brings together leading researchers from around the country and internationally who are carrying out exome and genome sequencing studies of bipolar disorder (BD). BD is a devastating mood disorder that imposes a significant burden on public health. It is among the most heritable serious mental disorders, with estimates ranging up to 90%. Yet, success in identifying susceptibility genes for BD has lagged noticeably behind other serious mental disorders such as schizophrenia. In this proposal, the BSC will share resources and sequence data for combined analyses that will advance the search for the genetic etiology of BD at a scale not possible by each of the research groups working by themselves. Recent efforts by the Psychiatric Genomics Consortium (PGC) using genome-wide association studies (GWAS) have begun to implicate common genetic variation in the risk for BD. However, GWAS miss the contribution of rarer genetic variation with minor allele frequencies <1%. It is hypothesized that rarer genetic variation may further contribute to the heritability of complex disorders like BD, and that identification of rarer genetic variation may more directly implicate underlying biological mechanisms in the etiology of BD. Advances in next generation sequencing technology are making it increasingly possible to sequence the exome or entire genome in large numbers of individuals in a costeffective manner. With this technology, studies can now interrogate the full spectrum of genetic variation and correlate it with disease. Researchers in the BSC are taking advantage of next generation sequencing to study BD in families with multiple affected relatives or in large numbers of unrelated cases and controls. In this proposal, we will assemble the largest existing collection of sequencing data on BD and carry out combined analyses of over 4,700 cases and 9,000 controls from 5 different case-control sequencing studies and over 200 families with over 1,000 affected relatives from 10 family sequencing studies. We will integrate the findings from the combined analyses with other on-going genomic, transcriptomic and proteomic studies to clarify the role of rare variants in the genetic architecture of BD and characterize the molecular and neurobiological mechanisms by which implicated rare variants and genes may contribute to risk for BD. We will then follow-up the top findings from our analyses and test them in an independent sample of over 5,000 cases and controls that will be made available to us through a new whole genome sequencing initiative. All summary data and results from the combined analyses will be freely shared via an on-line study resource with the research community. Next generation sequencing technology holds great promise for revealing the genetic architecture of complex psychiatric disorders. This proposal will build on the NIMH's considerable investment in sequencing to maximize our ability to explain the genetic contribution to BD and lay the needed foundation for improved treatment/prevention strategies.